Nitroxides (such as tempol) which have been used as EPR spin labels have been shown to exhibit superoxide dismutase (SOD) activity and are quite effective agents in protecting cells against a wide variety of oxidative stresses including hydrogen peroxide, superoxide, organic hydroperoxides, redox-cycling chemotherapy drugs, and ionizing radiation. We have demonstrated that Tempol protects both cells in vitro and mice against ionizing radiation. Thus, the nitroxides represent a new class of radiation protectors that may have widespread use in protecting humans against radiation. Importantly, we have shown that tempol does not protect rodent tumor tissue; the mechanism of which we believe involves differential metabolic reduction properties of normal versus tumor tissue. In vivo electron paramagnetic resonance imaging studies in a tumor-bearing animal model has shown more rapid reduction of nitroxides in tumor compared to normal tissue. Recent studies have shown that cells deficient in glucose 6 phosphate dehydrogenase (G6PD) reduce the nitroxide to the hydroxylamine much slower than control cells suggesting a role for this important biochemical pathway in nitroxide reduction. We have also recently shown that intracellular glutathione levels are a major determinant of nitroxide reduction in tissues. These studies will enable us to best determine the appropriate routes of administration for nitroxides as potentially selective radioprotectors of normal tissues. We have also recently shown that nitroxides protect against the cytotoxicity and mutagenicity of estrogen metabolites. These studies will be expanded to explore their impact to in vivo tumor models. Lastly, preliminary studies have indicated that long-term administration of tempol (in the food or drinking water) to p53 knockout mice extends their life span. Additionally in control mice we have observed that long-term administration of tempol results in dramatic weight reduction, which we have recently correlated, with increased expression of mitochondrial uncoupling protein 2 in skeletal muscle. Since nitroxides readily penetrate cell membranes and are potent antioxidants, they may be of use in other areas of medical research such as ischemia/reperfusion injury studies, prevention of cataracts, inflammatory processes, and aging.